Page 73 - 89Zr-Immuno-PET:Towards a Clinical Tool to Guide Antibody-based Therapy in Cancer

Initial clinical trials with 89Zr-immuno-PET in oncology
administration of 220 mg unlabeled trastuzumab, immediately followed by 10 mg 89Zr-trastuzumab, liver uptake was lowered (33% of the injected dose) and an
increase in uptake in the other tumor lesions, such as bone metastases, was
observed. Based on a theoretical calculation the authors conclude that a dose of
280 mg trastuzumab could only saturate 47% of all HER2 present in the liver
metastases of this patient, indicating a higher dose of trastuzumab is required to
saturate lesions in case of extensive HER2-positive tumor load. Based on this
important observation that pharmacokinetics and organ distribution can be
influenced by the extent of tumor load, dosing of trastuzumab for metastastic
breast cancer should be reconsidered. An individualized dosing schedule of 4 trastuzumab based on tumor load, guided by 89Zr-trastuzumab-PET, instead of
patient weight, might improve efficacy of treatment.
89Zr-trastuzumab to assess response by alteration of antigen expression
Gaykema et al. evaluated 89Zr-trastuzumab-PET to determine alteration of HER2 expression after anti-angiogenic treatment with the novel heat shock protein 90 (HSP90) inhibitor NVP-AUY922 in 10 patients with HER2-positive breast cancer (24). HSP90 inhibition can deplete client proteins like HER2. This study was performed with 37 MBq 89Zr-trastuzumab (50 mg), while NVP-AUY922 was administered i.v. in a weekly schedule of 70 mg/m2. Change in tumor uptake of 89Zr-trastuzumab at baseline versus 3 weeks on treatment was correlated to change in size on CT after 8 weeks treatment. This feasibility study suggests that 89Zr- immuno-PET can be used to monitor alteration of antigen expression and supports further evaluation of 89Zr-trastuzumab-PET in providing insight in treatment response of novel anti-cancer agents like the HSP90 inhibitor NVP-AUY922 in larger studies.
89Zr-trastuzumab-PET as predictive imaging biomarker for ADC treatment
Recently, the ADC trastuzumab-emtansine (T-DM1) was approved for treatment of patients with progression of HER2-positive breast cancer, previously treated with trastuzumab-based therapy. The ZEPHIR study investigated the use of 89Zr- trastuzumab-PET, combined with early response assessment with FDG-PET, as a predictive imaging biomarker for treatment with T-DM1 (25). In this study intra- and interpatient heterogeneity in HER2 mapping of metastatic disease was also explored, see Figure 2. The study was performed by administration of 37 MBq 89Zr-trastuzumab (50 mg). 89Zr-trastuzumab-PET scans were acquired 4 days p.i.
71